Systemic LE (SLE) may be a prototypic multisystem autoimmune disease where interplay of environmental and genetic risk factors results in progressive loss of tolerance to nuclear antigens over time, finally culminating in clinical disease. The heterogeneity of clinical manifestations and therefore the disease’s unpredictable course characterized by flares and remissions are very likely a mirrored image of heterogeneity at the origin of disease, with a final common pathway resulting in loss of tolerance to nuclear antigens. Impaired clearance of immune complexes and apoptotic material and production of autoantibodies have long been recognized as major pathogenic events during this disease. Over the past decade the sort I interferon cytokine family has been postulated to play a central role in SLE pathogenesis, by promoting feedback loops progressively disrupting peripheral immune tolerance and driving disease activity.